In order to provide an experimental foundation for developing a new approach to the diagnosis and pathophysiological investigation of herpes simplex virus type 1 (HVS-1) encephalitis, we will carry out a series of studies in a rat model. Using the method of quantitative autoradiography, we will examine the regional brain uptake and sequestration of 14C-labeled 2'-fluoro-pyrimidine antiviral nucleosides in focal HSV-1 encephalitis. To more accurately construct and test a mathematical model of drug delivery and sequestration within infected brain regions, we will carry out further studies with the potent antiviral 2'-fluoro-5-methyl-1-Beta-D-arabinosyluracil (FMAU) labeled with 14C, assessing regional brain concentrations of the drug at short time intervals after drug injection. To test the feasibility of translating this strategy to imaging of human encephalitis using positron emission tomography (PET), we will next assess the capacity of 14C-labeled mono-, di- and tri-fluoromethyl derivatives of FMAU for their capacity to selectively image focal HSV-1 infection in the rat brain. These compounds are chosen because they can eventually be practically labeled with 18F for human PET studies if the present animal studies indicate that they share with FMAU the capacity for sensitive and specific uptake into infected brain regions. In order to provide background information necessary for interpretation of the antiviral studies and of our model, we will also characterize regional alterations in blood-brain barrier permeability and cerebral blood flow using autoradiographic methods. This series of studies will provide unique information bearing on the pathogenesis of HSV-1 encephalitis and on the delivery and local metabolism of antiviral drugs within infected brain regions. We are hopeful that they will also lead to a sorely needed new method of diagnosing human herpes encephalitis and perhaps to more rational drug therapy for the disease.